The proposed project will build on the progress that has been made during the past grant periods in the analysis of connectional networks that link architectonic areas of the orbital and medial prefrontal cortex (OMPFC) in monkeys. The areas within these orbital and medial networks have differential connections both with other cortical areas and with subcortical structures such as the thalamus, amygdala, hypothalamus and periaqueductal gray. In humans, positron emission tomography (PET) studies indicate that the areas of the OMPFC have abnormal levels of activity in psychiatric disorders such as unipolar and bipolar depression. In the next grant period the further connections of the networks of the OMPFC with cortical areas in the dorsolateral PFC and the temporal cortex will be defined in monkeys with anterograde axonal tracers injections into the target structures. Connections from the medial and orbital networks to the striatum will also be defined in the same experiments, and in experiments with retrograde axonal tracers injected into the accumbens and caudate nuclei and the putamen. In order to correlate the observations in monkeys with imaging studies in humans, the architectonic areas that have been identified in monkeys will be defined in human brains, using the multiple staining methods that were used in monkeys. The monkey and human maps will be further correlated with the aid of computer generated unfolded maps of the frontal lobe. The role of the human OMPFC in clinical depression will be further studied in two projects. In the first, autopsy brain tissue from control subjects or from subjects diagnosed with unipolar or bipolar depression or schizophrenia will be studies to determine cortical volume and cell number in the defined architectonic areas in the subgenual or medical orbital cortex. In the second, architectonic areas will be outlined on MRI images of brains from depressed or control suects that were previously studied with PET. By correlating the PET and MRI images, levels of metabolic and synaptic activity can be determined within the defined architectonic areas as a function of unipolar or bipolar depression.